The present study addresses the following portion of NICHD's mission statement: "To contribute to the prevention and amelioration of mental retardation and developmental disabilities." We propose to test the hypothesis that the key thyroid-related factor in early fetal brain development is thyroxine (T4), derived from the mother. According to this hypothesis, low circulating maternal levels of free T4 may adversely influence fetal brain development, even when the mother has normal TSH levels. A biological basis for this is demonstrated in animal studies. Pop's work and our earlier work provide preliminary evidence in humans. Our aim is to determine whether low free T4 levels in euthyroid women during pregnancy are associated with suboptimal neuropsychological development in their offspring. This extends our earlier work showing a relationship between maternal thyroid deficiency during pregnancy (defined by elevated TSH levels) and lower IQ in offspring. The proposed prospective observational study involves obtaining initial consent from, and recruiting, 12,300 early second trimester women whose serum samples are being sent to our laboratory for routine prenatal screening. TSH measurements will be performed in all enrollees' samples and the provider informed if the result indicates possible hypo- or hyperthyroidism. These 300 estimated women will not be eligible for further participation. Free T4, will be measured in stored samples from the remaining 12,000 euthyroid women, after completion of the pregnancy. A nested case-control study design will then be used, as follows: after delivery, the 120 women with free T4 measurements below the 1st centile will each be matched with a woman whose free T4 values are between the 10th and 90th centiles. The women will be contacted and again asked to consent to participate; their children will then undergo neurodevelopmental testing at two years of age. An estimated 100 cases and 100 matched controls will complete the protocol. Scores of children of the women with low free T4 during pregnancy are hypothesized to average at least 6 points lower than controls on both mental and psychomotor components of the Bayley Scale. The study has an 80% power to detect this difference. If the hypothesized effect is found, the primary benefit would be that strategies could be designed and tested for identifying and treating high risk women to avoid adverse consequences in their children. It is intended that the study be continued for five more years (total of 10) in order to obtain additional estimates of neuropsychological development in the children at a time when more extensive testing can be performed.